Frimley GuidelinesFrimley Health Guidelines

Sacubitril Valsartan (ARNI), Initiation and Titration

Initiation and Titration of Sacubitril / Valsartan,Entresto® (ARNI) in Adults with Heart Failure with Reduced Ejection Fraction (HFrEF) previously known as Left Ventricular Systolic Dysfunction (LVSD)

Key Points

This advice applies to monitoring of pharmacotherapy in clinically stable patients; it does NOT apply to patients with intercurrent acute illness
Please ensure patient has a genuine AKI (rapidly deteriorating renal function) before prognostic medication is discontinued
If prognostic medication is stopped due to AKI/acutely unwell patient, please consider restarting if renal function recovers

Version:	4
Date Issued:	27/06/2025
Review Date:	01/07/2028
Key words:	Angiotensin receptor-neprilysin inhibitor (ARNI), initiation, titration.

This is a controlled document. If you are using a printed copy, check it against the guidelines site to ensure you are using the latest edition. Print copies must be destroyed after use.

Abbreviations

ACEI	Angiotensin converting enzyme inhibitors
AKI	Acute kidney injury
ARB	Angiotensin receptor blocker
ARNI	Angiotensin receptor neprilysn Inhibitor
BP	Blood pressure
CKD	Chronic Kidney disease
eGFR	Estimated glomerular filtration rate
HFrEF	Heart failure reduced ejection fraction
HFmrEF	Heart failure with mildly reduced ejection fraction
K	Potassium
MRA	Mineralocorticoid receptor antagonists
NSAIDs	Nonsteroidal anti-inflammatory drugs
OTC	Over the counter
PVD	Peripheral vascular disease
SBP	Systolic blood pressure

Evidence from PARADIGM-HF TRIAL (2014) demonstrated that patients with heart failure with reduced ejection fraction (LVEF<35%) and NYHA class II-IV treated with sacubitril/valsartan versus standard of care (ACEI-enalapril) had reduced mortality risk and reduced risk of heart failure hospitalisation. NICE guidance supports replacing ACEI or ARB with sacubitril/valsartan for patients who have EF<35%, NYHA II-IV and who are established on and tolerating ACEI or ARB.

Sacubitril is a neprilysin inhibitor working to block the breakdown of natriuretic peptides.

Contra-indications

Cautions

Bilateral renal   artery stenosis, refer patients for advice



Aortic or mitral   valve stenosis or obstructive cardiomyopathy, refer patients for advice



Known   hypersensitivity to ARB, sacubitril or excipients



Hereditary or   idiopathic angioedema



Concomitant use   with ACEI



Second and third   trimesters of pregnancy (not recommended in first trimester)



Baseline potassium   > 5.4 mmol/l



Concomitant use   with ACEI or ARB



Known history of   angioedema to ACEI or ARB therapy



Concomitant use   with aliskiren containing products in patients with diabetes mellitus or in   patients with eGFR<60ml/min



Severe hepatic   impairment, biliary cirrhosis and cholestasis, end stage renal failure

Systolic   BP<100mmHg

Patients with a   documented intolerance of ACEI due to symptomatic hypotension - consider   re-challenging with a longer acting ACEI (such as perindopril). Care if   asymptomatic hypotension (systolic BP< 90mmHg)



Patients on high   dose diuretics (i.e., furosemide > 80mg daily) – increased risk of   hypotension and renal dysfunction



Breast feeding -   suggest avoid



Dose reduction   suggested for patients with renal impairment, eGFR 30-60ml/min



Limited clinical   experience for eGFR<30ml/min



Baseline potassium   > 5 to 5.3mmol/l



Concomitant   aliskiren use not meeting contra indications



Moderate hepatic   impairment (Child-Pugh B classification) or with AST/ALT values more than   twice the upper limit of normal

Angioedema

Rare but life threatening. Discontinue therapy and seek immediate advice from accident and emergency. Sacubitril/valsartan must not be re-administered.

Symptomatic hypotension

If no signs of fluid retention, reduce the dose of diuretic.
Consider dehydration and address as appropriate
If dizziness and light-headedness and/or confusion occur, consider stopping nitrates, calcium channel blockers and other vasodilators first, and then consider reducing dose of beta-blocker. Monitor closely and allow longer intervals between dose titrations. Consider reduction of sacubitril/valsartan dose to the previous tolerated dose.

Seek specialist advice if these measures do not resolve symptomatic hypotension

Asymptomatic hypotension

Does not usually warrant a change in therapy, but BP requires monitoring and watch for worsening renal function.

Persistent dry cough

Review aetiology of cough, e.g., due to smoking, worsening heart failure/pulmonary oedema, respiratory disease
Review cough tolerability versus benefits of sacubitril/valsartan

May require stopping treatment. ARB alone may be tolerated

Worsening renal function

ARNI are disease modifying drugs in patients with HFrEF so they improve patient outcomes. The risk of stopping or reducing dose is, in general, likely to be of greater detriment to a patient’s prognosis than a modest increase in serum creatinine, or mild hyperkalaemia.

These guidelines are generally for management of CKD

An increase in urea, creatinine and K+ is to be expected after initiation/titration of ARNI. If the increase is small and asymptomatic, no action is necessary. Please see the table below for recommended actions.

Please ensure patient has a genuine AKI (rapidly deteriorating renal function) before prognostic medication is stopped.

If prognostic medication is stopped due to AKI/acutely unwell patient, please consider restarting if renal function recovers. Please liaise with the heart failure team for further advice.

Potassium	Action
Mild hyperkalaemia (5.5 – 5.9mol/L) Management depends on clinical context	If the patient is acutely unwell, or has AKI, stop the ARNI and consider referral to hospital If the patient is clinically stable (i.e. the test was done as a routine check, and there is no AKI warning stage test result), undertake medication review. If hyperkalaemia is unexpected, consider arranging a repeat test within 3 days, taking steps to minimise any of the factors that can cause artifactual hyperkalaemia Look for and remove other contributors to hyperkalaemia, including; trimethoprim/co-trimoxazole, potassium supplements, potassium-sparing diuretics, salt substitutes e.g. ‘LoSalt’, NSAIDs, non-selective beta-blockers, digoxin toxicity Review the patient clinically: reduce/stop diuretics if evidence of over-diuresis. Consider halving dose of ARNI, and review indications Provide patients with a diet advice sheet on reduction of potassium intake. If problems with hyperkalaemia persist, refer to renal medicine for dietetic advice Consider seeking advice from local heart failure specialist team if the indication for treatment was HFrEF
Moderate hyperkalaemia (6.0-6.4mmol/L) Management depends on clinical context	Stop ARNI If the patient is acutely unwell, or has AKI refer to hospital for immediate assessment Re-start at lower dose once serum K≤5.5 mmol/L and continue to monitor. If the patient is clinically stable (i.e., the test was done as a routine check rather than for acute illness, and there is no AKI warning stage test result), undertake medication review within 1 working day of the result. If patient on combination of ARNI with MRA only restart one of these drugs at a time. If hyperkalaemia is unexpected, consider arranging a repeat test the following day taking steps to minimise any of the factors that can cause artefactual hyperkalaemia. Look for and remove other contributors to hyperkalaemia as indicated in ‘mild hyperkalaemia’ Review the patient clinically reduce/stop diuretics if evidence of over diuresis.
Severe hyperkalaemia (≥ 6.5 mmol/L)	Stop ARNI Refer to hospital (via A&E) for immediate assessment and treatment

Creatinine	Action
Creatinine ↑ > 15% but <30% from initial baseline	Continue, but repeat U&Es in a further 1 to 2 weeks Arrange clinical review including assessment of fluid status and blood pressure Try to continue ARNI treatment Reduce or stop other BP lowering drugs (eg. calcium channel blockers, alpha blockers) if SBP <120 mmHg Reduce concurrent diuretics if there is clinical evidence of hypovolaemia/overdiuresis If the patient is acutely unwell, or has AKI consider stopping the ARNI
Creatinine increases at any point by ≥ 30% from initial baseline	Arrange clinical review including assessment of fluid status and blood pressure Consider try to continue ARNI treatment Reduce or stop other BP lowering drugs (eg. calcium channel blockers, alpha blockers) if SBP <120 mmHg Reduce concurrent diuretics if there is clinical evidence of hypovolaemia/overdiuresis Re-check renal function within 5-7 days If the patient is acutely unwell, or has AKI, consider stopping the ARNI and referral to hospital
If serum creatinine remains >30% from initial baseline with above measures	Stop the ARNI or reduce the dose to a previously tolerated dose and re-check renal function in 5-7 days; add an alternative antihypertensive medication if required Obtain advice from local heart failure specialist team if the indication for treatment was heart failure with reduced ejection fraction: continuing an ARNI in HFrEF may be beneficial even if serum creatinine rises by >30% Consider obtaining advice from nephrology, even if serum creatinine returns to baseline If the patient is acutely unwell, or has AKI, stop the ARNI and consider referral to hospital

Version:	4
Guidelines Lead(s):	Dr Lydia Sturridge, Consultant Cardiologist
Contributor(s):
Lead Director / Chief of Service:	Dr Peter Clarkson, CoS for Cardiology
Library check completed:	8 March 2022
Ratified at:	Cardiologist Clinical Governance 18/06/2025
Date Issued:	27/06/2025
Review Date:	01/07/2028
Pharmaceutical dosing advice and formulary compliance checked by:	Alexandra Kirke, Lead Cardiology Pharmacist, 6 May 2025
Key words:	Angiotensin receptor-neprilysin inhibitor (ARNI), initiation, titration

This guideline has been registered with the Trust. However, clinical guidelines are guidelines only. The interpretation and application of clinical guidelines will remain the responsibility of the individual clinician. If in doubt, contact a senior colleague or expert. Caution is advised when using guidelines after the review date.
This guideline is for use in Frimley Health NHS Foundation Trust hospitals only. Any use outside this location will not be supported by the Trust and will be at the risk of the individual using it.

Version Control Sheet

Version	Date	Guideline Lead(s)	Status	Comment
2	September 2018	Dr Lydia Sturridge, Ann Parker	Final	Ratified at APC
3	February 2022	Dr Lydia Sturridge, Ann Parker	Final	Changed to new format and references checked by Library team.
4	June 2025	Dr Lydia Sturridge	Final	Scheduled review

Key Points

Guideline Rationale

Important Drug Interactions

Initiation and monitoring

Dose Titration

Problem Solving

Angioedema

Symptomatic hypotension

Asymptomatic hypotension

Persistent dry cough

Worsening renal function

Patient information

References

Full version control record